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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of HPEC senescent vs immortalized cells

ABSTRACT: Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype, a critical feature in tumorigenesis. The inactivation of multiple pathways that positively regulate senescence are required for immortalization. To identify these pathways in an unbiased manner, we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells (HPECs) passaged to senescence. These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein. Senescent cells display gene expression patterns that reflect their nonproliferative, differentiated phenotype and express secretory proteases and extracellular matrix components. A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples. Thus, these genes may function in novel pathways that regulate senescence and are inactivated during immortalization. These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo.

ORGANISM(S): Homo sapiens

SUBMITTER: Samuel DePrimo

PROVIDER: E-SMDB-6 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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HPEC senescent vs immortalized cells

Project description:Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype, a critical feature in tumorigenesis. The inactivation of multiple pathways that positively regulate senescence are required for immortalization. To identify these pathways in an unbiased manner, we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells (HPECs) passaged to senescence. These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein. Senescent cells display gene expression patterns that reflect their nonproliferative, differentiated phenotype and express secretory proteases and extracellular matrix components. A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples. Thus, these genes may function in novel pathways that regulate senescence and are inactivated during immortalization. These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed

2005-10-18 | E-GEOD-3460 | biostudies-arrayexpress

HPEC senescent vs immortalized cells

2005-10-18 | GSE3460 | GEO

Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization

Project description:Progression to malignancy requires cells to overcome senescence and switch to an immortal phenotype. Thus, exploring the genetic and epigenetic changes that occur during senescence/immortalization may help elucidate crucial events that lead to cell transformation. In the present study, we have globally profiled DNA methylation in relation to gene expression in primary, senescent and immortalized mouse embryonic fibroblasts. Primary, senescent and immortalized mouse fibroblasts obtained from three independent embryos. Compare immortalized versus primary and senescent versus primary cells.

2012-11-29 | E-GEOD-39034 | biostudies-arrayexpress

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Project description:Activated Ha-ras was introduced to HMF3A cells. HMF3A cells are conditionally immortalised human mammary fibroblasts. They undergo co-ordinated senescence upon inactivation of LT antigen, when cultured at 39C. The introduction of Ras did not prevent this but affected the molecular profile. Keywords = Senescence Keywords = fibroblast Keywords = Ras Keywords = immortalization Keywords = transformation

2010-06-09 | E-GEOD-979 | biostudies-arrayexpress

Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization

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Viral integration promotes SV40T-induced immortalization by disturbing the expression of DNA/chromosome- and ECM-associated functional genes

Project description:Lentivirus containing simian virus 40 large T antigen (SV40T) is routinely used to induce cell immortalization. However, the roles of viral integration itself in this progress is still controversial. Here, we transformed primary mouse embryonic fibroblasts (MEFs) with SV40T lentivirus and studied the roles of viral integration in the immortalization using RNA-seq and whole genome sequencing (WGS). During the immortalization, differentially expressed genes (DGEs) are enriched in viral infection and several diverse activities. However, DEGs between immortalized and aging cells are significantly enriched in DNA/chromosome- and extracellular matrix (ECM)-associated activities. Gene regulatory network (GRN) analysis shows that although p53 is a key regulatory factor, many other transcription factors also play critical roles in the process, like STAT1. Of these DEGs, 32 genes have viral integration in their coding and/or regulatory regions. Our findings suggest that viral integration may promote SV40T-mediated immortalization by disturbing the expression of DNA/chromosome- and ECM-associated genes.

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DNA methylation patterns separate senescence from malignant transformation potential in human cells [gene expression]

Project description:Replicative senescent cells reportedly share similar DNA methylation changes with cancer cells, which are purported to facilitate tumorigenesis in cells bypassing senescence. However, we now report biologically critical and distinct patterns of DNA methylation evolution between replicative and oncogene-induced senescence and transformation in a classic human cell transformation model. While overall DNA methylation losses and gains occur in both replicative senescent and transformed cells, the patterns evolve more programmatically for the former and stochastically for the latter. Oncogene-induced senescence is an acute process involving minimal changes to DNA methylation. The stochastic DNA methylation alterations in transformation mainly involve a set of pro-survival promoter CpG-island methylation events targeting genes controlling development and differentiation processes, while the senescence-specific promoter changes occur in genes involved in positive regulation of cellular biosynthesis and macromolecular metabolism. The above set of pro-survival promoter CpG-island hypermethylation events, but not the senescence-specific events, are prone to occur in primary tumors and aging tissues. Importantly, cells manifest senescence-specific epigenomic patterns very early during commitment to senescence, and while these “near-senescent” cells can be immortalized, they are refractory to transformation by H-Ras oncoprotein (H-rasV12). The senescence-specific methylation is retained during immortalization and transformation attempts, suggesting it does not function to promote tumorigenesis. Thus, abnormalities in cancer-related methylation has their origins in aging and not replicative senescence, and senescence-associated methylation potentially prevents malignant transformation.

2018-01-31 | GSE91070 | GEO

DNA methylation patterns separate senescence from malignant transformation potential in human cells [methylation]

2018-01-31 | GSE91069 | GEO

Gene expression signature of c-MYC-immortalized human fibroblasts reveals loss of growth inhibitory response to TGFb

Project description:Cancer cells exhibit the ability to proliferate indefinitely, but paradoxically, overexpression of cellular oncogenes in primary cells can result in a rapid and irreversible cell cycle arrest known as oncogene-induced senescence (OIS). However, we have shown that constitutive overexpression of the oncogene c-MYC in primary human foreskin fibroblasts results in a population of cells with unlimited lifespan; these immortalized cells are henceforth referred to as iMYC. Here, in order to further elucidate the mechanisms underlying the immortalization process, a gene expression signature of three independently established iMYC cell lines compared to matched early passage c-MYC overexpressing cells was derived. Network analysis of this "iMYC signature" indicated that a large fraction of the down-regulated genes were functionally connected and major nodes centered around the TGFb, IL-6 and IGF-1 signaling pathways. Here, we focused on the functional validation of the alteration of TGFb response during c-MYC-mediated immortalization. The results demonstrate loss of sensitivity of iMYC cells to activation of TGFb signaling upon ligand addition. Furthermore, we show that aberrant regulation of the p27 tumor suppressor protein in iMYC cells is a key event that contributes to loss of response to TGFb. These findings highlight the potential to reveal key pathways contributing to the self-renewal of cancer cells through functional mining of the unique gene expression signature of cells immortalized by c-MYC. Cell Cycle. 2011 Aug 1;10(15).

2011-08-04 | GSE31002 | GEO

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